1. Technical Field
The present invention relates to cyclic amine derivatives and more particularly it relates to chemokine receptor antagonists capable of expecting effects as remedies and/or prophylactics for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, cardiomyopathy, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, allergic rhinitis and allergic dermatitis wherein infiltration of blood leukocyte components such as monocytes or lymphocytes into tissues plays a principal role in progression and maintenance of diseases.
2. Background Art
Chemokines are a generic name of a group of inflammatory/immunomodulatory polypeptides having a molecular weight of 6 to 15 KD and produced in inflammatory sites by various kinds of cells, for example, macrophages, monocytes, eosinophils, neutrophils, fibroblasts, vascular endothelial cells, smooth muscle cells and mast cells. The chemokines are classified into two major subgroups of CXC chemokines (or α-chemokines) and CC chemokines (or β-chemokines) by the common location of four preserved cysteine residues and a difference in chromosomal locations of genes encoding the chemokines. The first two cysteines of the CXC chemokines are separated by one amino acid; however, the same cysteines of the CC chemokine are adjacent. For example, IL-8 (an abbreviation for interleukin-8) is the CXC chemokines. On the other hand, MIP-1 α/β (an abbreviation for macrophage inflammatory protein-1 α/β), MCP-1 (an abbreviation for monocyte chemoattractant protein-1) and RANTES (an abbreviation for regulated upon activation, normal T-cell expressed and secreted) are cited as the CC chemokines.
Furthermore, there also exist chemokines which do not fall into either of chemokine subgroups. Lymphotactin having only two cysteines and classified as C chemokines and fractalkine classified as CX3C chemokines because the first two cysteines are separated by three amino acids and having a chemokinelike domain in the mucin structure are cited as such a chemokine. The chemokines promote cell migration and have expression enhancing actions on cellular adhesion molecules such as integrins and further cellular adhesion enhancing actions. Therefore, the chemokines are thought to be protein factors closely involved in the adhesion and infiltration of leukocytes or the like into the pathogenic sites such as inflammatory tissues. See, for example, The Chemokine Facts Book, by Vaddi, K. et al., Academic Press, 1997; Chemoattractant Ligand and Their Receptors, edited by Horuk, R., CRC Press, 1996; Ward, G. W. et al., Biochem. J., 1998, 333, 457; Luster, A. D., New Engl. J. Med., 1998, 338, 436; Bagglioni, M., Nature, 1998, 392, 565; Rolins. B. J., Blood, 1997, 90, 909; Alam, R., J. Allergy Clin. Immunol., 1997, 99, 273; Hancock, W. W., Am. J. Pathol., 1996, 148, 681; Taub, D. D., Cytokine & Growth Factor Rev., 1996, 7, 335; Strieter, R. M. et al., J. Immunol., 1996, 156, 3583; Furie, M. B. et al., Am. J. Pathol., 1995, 146, 1287; Schall, T. J. et al., Current Opinion in Immunology, 1994, 6, 865; and Edginton, S. M., Biotechnology, 1993, 11, 676 as references.
For example, MIP-1 α causes a transient increase in intracellular calcium ion concentration levels and induces cell migration of T lymphocytes or B lymphocytes (see, for example, Tabu, D. D. et al., Science, 1993, 260, 355 and Shall, T. J. et al., J. Exp. Med., 1993, 177, 1821), cell migration of eosinophils (see, for example, Rot, A. et al., J. Exp. Med., 1992, 176, 1489), cell migration of NK cells (see, for example, Magazachi, A. A. et al., J. Immunol., 1994, 153, 4969), expression of integrins (see, for example, Vaddi, K. et al., J. Immunol., 1994, 153, 4721) and differentiation of osteoclasts (see, for example, Kukita, T. et al., Lab. Invest., 1997, 76, 399). MIP-1 α also increases the IgE and IgG4 production in B cells (see, for example, Kimata, H. et al., J. Exp. Med., 1996, 183, 2397) and inhibits the proliferation of hematopoietic stem cells (see, for example, Mayani, H. et al., Exp. Hematol., 1995, 23, 422; Keller, J. R. et al., Blood, 1994, 84, 2175; Eaves, C. J. et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 12015; Bodine, D. M. et al., Blood, 1991, 78, 914; and Broxmeyer, H. E. et al., Blood, 1990, 76, 1110).
As to the association of MIP-1 α with in vivo actions or pathogenesis of diseases, it has been reported that the MIP-1 α is a pyrogen in rabbits (see, for example, Davatelis, G. et al., Science, 1989, 243, 1066) and the injection of the MIP-1 α into the footpads of mice results in inflammatory reactions such as infiltration of neutrophils or mononuclear cells (see, for example, Alam, R. et al., J. Immunol., 1994, 152, 1298).
It has been also reported that a neutralizing antibody to MIP-1 α has inhibitory effects or remedial effects in animal models of granuloma (see, for example, Lukacs, N. W. et al., J. Exp. Med., 1993, 177, 1551), asthma (see, for example, Lukacs, N. W. et al., Eur. J. Immunol., 1995, 25, 245 and Lukacs, N. W. et al., J. Immunol., 1997, 158, 4398), multiple sclerosis (see, for example, Karpus, W. J. et al., J. Immunol., 1995, 155, 5003 and Karpus, W. J. et al., J. Leukoc. Biol., 1997, 62, 681), idiopathic pulmonary fibrosis (see, for example, Smith, R. E. et al., J. Immunol., 1994, 153, 4704 and Smith, R. E., Biol. Signals, 1996, 5, 223), acute lung injury (see, for example, Shanley, T. P. et al., J. Immunol., 1995, 154, 4793 and Standiford, T. J. et al., J. Immunol., 1995, 155, 1515) and rheumatoid arthritis (see, for example, Kasama, T. et al., J. Clin. Invest., 1995, 95, 2868) and the like. Furthermore, it has been reported that coxsackie virus infection-induced myocarditis or herpes stromal keratitis is inhibited in MIP-1α gene deficient mice (see, for example, Cook, D. N. et al., Science, 1995, 269, 1583 and Tumpey, T. M. et al., J. Virology, 1998, 72, 3705).
In addition, significant expression of MIP-1 α was recognized in patients such as chronic pulmonary inflammatory diseases (see, for example, Standiford, T. J. et al., J. Immunol., 1993, 151, 2852), hypersensitivity pneumonitis (see, for example, Denis, M., Am. J. Respir. Crit. Care Med., 1995, 151, 164), rheumatoid arthritis (see, for example, Koch, A. E. et al., J. Clin. Invest., 1994, 93, 921), infectious meningitis (see, for example, Lahrtz, F. et al., J. Neuroimmunol., 1998, 85, 33) and chronic inflammation of muscle (see, for example, Adams, E. M. et al., Proc. Assoc. Am. Physicians, 1997, 109, 275). The studies indicate that MIP-1 α is deeply involved in the local accumulation of various subtypes of leukocytes in association with initiation, progression and maintenance of inflammatory diseases.
MCP-1 [also known as MCAF (an abbreviation for macrophage chemotactic and activating factor) or JE] is a CC chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts and vascular endothelial cells and has a cell migration activity and cell adhesion enhancing actions on monocytes (see, for example, Valente, A. J. et al., Biochemistry, 1988, 27, 4162; Matsushima, K. et al., J. Exp. Med., 1989, 169, 1485; Yoshimura, T. et al., J. Immunol., 1989, 142, 1956; Rollins, B. J. et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B. J. et al., Blood, 1991, 78, 1112; Jiang, Y. et al., J. Immunol., 1992, 148, 2423; and Vaddi, K. et al., J. Immunol., 1994, 153, 4721), memory T lymphocytes (see, for example, Carr., M. W. et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652), T lymphocytes (see, for example, Loetscher, P. et al., FASEB J., 1994, 8, 1055) and natural killer cells (NK cells) (see, for example, Loetscher, P. et al., J. Immunol., 1996, 156, 322 and Allavena, P. et al., Eur. J. Immunol., 1994, 24, 3233) or the like and MCP-1 further has actions as a histamine releasing factor from basophils (see, for example, Alam R. et al., J. Clin. Invest., 1992, 89, 723; Bischoff, S. C. et al., J. Exp. Med., 1992, 175, 1271; and Kuna, P. et al., J. Exp. Med., 1992, 175, 489).
Moreover, remarkable expression of MCP-1 has been reported in diseases in which the accumulation of monocytes/macrophages and/or T cells is thought to be deeply involved in initiation, progression and maintenance of lesions such as atherosclerosis (see, for example, Hayes, I. M. et al., Arterioscler. Thromb, Vasc. Biol., 1998, 18, 397; Takeya, M. et al., Hum. Pathol., 1993, 24, 534; Yla-Herttuala, S. et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; and Nelken, N. A., J. Clin. Invest., 1991, 88, 1121), rheumatoid arthritis (see, for example, Koch, A. E. et al., J. Clin. Invest., 1992, 90, 772; Akahoshi, T. et al., Arthritis Rheum., 1993. 36, 762; and Robinson, E. et al., Clin. Exp. Immunol., 101, 398), nephritis (see, for example, Noris, M. et al., Lab. Invest., 1995, 73, 804; Wada, T. et al., Kidney Int., 1996, 49, 761; and Gesualdo, L. et al., Kidney Int., 1997, 51, 155), nephropathy (see, for example, Saitoh, A. et al., J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama, H. et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis and pulmonary sarcoidosis (see, for example, Sugiyama, Y. et al., Internal Medicine, 1997, 36, 856), asthma (see, for example, Karina, M. et al., J. Invest. Allergol. Clin. Immunol., 1997, 7, 254; Stephene, T. H., Am. J. Respir. Crit. Care Med., 1997, 156, 1377; and Sousa, A. R. et al., Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see, for example, McManus, C. et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (see, for example, Gillitzer, R. et al., J. Invest. Dermatol., 1993. 101, 127), inflammatory bowel disease (see, for example, Grimm, M. C. et al., J. Leukoc. Biol., 1996, 59, 804 and Reinecker, H. C. et al., Gastroenterology, 1995, 106, 40), cardiomyopathy (see, for example, Seino, Y. et al., Cytokine, 1995, 7, 301), endometriosis (see, for example, Jolicoeur, C. et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesion (see, for example, Zeyneloglu, H. B. et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see, for example, Aurust, P. et al., Circulation, 1998, 97, 1136), chronic liver disease (see, for example, Marra, F. et al., Am. J. Pathol., 1998, 152, 423), viral meningitis (see, for example, Lahrtz, F. et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see, for example, Wong, M. et al., J. Rheumatol., 1997, 24, 1179) and sepsis (see, for example, Salkowski, C. A. et al., Infect. Immun., 1998, 66, 3569).
The inhibitory effects or remedial effects of an anti-MCP-1 antibody have been reported in animal models such as rheumatoid arthritis (see, for example, Schimmer, R. C. et al., J. Immunol., 1998, 160, 1466; Schrier, D. J., J. Leukoc. Biol., 1998, 63, 359; and Ogata H. et al., J. Pathol., 1997, 182, 106), multiple sclerosis (see, for example, Karpus, W. J., J. Leukoc. Biol., 1997, 62., 681), nephritis (see, for example, Lloyd, C. M. et al., J. Exp. Med., 1997, 185, 1371 and Wada T. et al., FASEB J., 1996, 10, 1418), asthma (see, for example, Gonzalo, J.-A. et al., J. Exp. Med., 1998, 188, 157 and Lukacs, N. W., J. Immunol., 1997, 158, 4398), atherosclerosis (see, for example, Guzman, L. A. et al., Circulation, 1993, 88 (suppl.), I-371), delayed type hypersensitivity (see, for example, Rand, M. L. et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (see, for example, Kimura, H. et al., Lab. Invest., 1998, 78, 571) and intraperitoneal adhesion (see, for example, Zeyneloglu, H. B. et al., Am. J. Obstet. Gynecol., 1998, 179, 438).
Further, it has been reported that MCP-1 (9-76) which is a peptide antagonist of MCP-1 inhibits arthritis in the mouse model (see, for example, Gong, J.-H., J. Exp. Med., 1997, 186, 131) and that MCP-1 is essential to monocyte mobilization in vivo in studies on MCP-1 gene deficient mice (see, for example, Lu, B. et al., J. Exp. Med., 1998, 187, 601 and Gu, L. et 41., Moll. Cell, 1998, 2, 275).
These data indicate that chemokines such as MIP-1 α and MCP-1 accumulate monocytes, lymphocytes or the like in disease sites and activate the cells and thus strongly suggest that the chemokines are deeply associated with initiation, progression and maintenance of diseases wherein monocytes, lymphocytes and the like are assumed to be deeply associated with the progression of lesion, for example, atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease and sepsis (see, for example, Rovin, B. H. et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C. et al., Curr. Opin. Nephrol. Hypertens., 1998, 7, 281; Conti, P. et al., Allergy and Asthma Proc., 1998, 19, 121; Ransohoff, R. M. et al., Trends Neuroscience., 1998, 21, 154; and MacDermott, R. P. et al., Inflammatory Bowel Diseases, 1998, 4, 54). A drug which inhibits actions of chemokines on target cells, therefore, can be expected to be useful as remedies and/or prophylactics for the diseases.
On the other hand, the cloning of genes encoding specific receptors for chemokines has been promoted, and it has become apparent that the receptors are G protein-coupled seven-transmembrane receptors present on various leukocytes. At least 5 CXC chemokine receptors (CXCR1 to CXCR5) and eight CC chemokine receptors (CCR1 to CCR8) have hitherto'been specified. For example, IL-8 is a ligand of CXCR1 and CXCR2. MIP-1 α is a ligand of CCR1 and CCR5, and MCP-1 is a ligand of CCR2A and CCR2B (see, for example, Holmes, W. E. et al., Science, 1991, 253, 1278-1280; Murphy, P. M. et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, I. F. et al., Proc. Natl. Acad. Sci., USA, 1994, 91, 2752-2756; Yamagami, S. et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C. et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494; Power, C. A. et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M. et al., Biohemistry, 1996, 35, 3362-3367; and Murphy, P. M. et al., Annual Review of Immunology, 1994, 12, 592-633).
Further, it has been reported that the pulmonary inflammation and granuloma are suppressed in CCR1 gene deficient mice (see, for example, Gao, J.-L. et al., J. Exp. Med., 1997, 185, 1959 and Gerard, C. et al., J. Clin. Invest., 1997, 100, 2022) and that accumulation of macrophages and formation of atherosclerotic lesions are decreased in CCR2 gene deficient mice (see, for example, Boring, L. et al., Nature, 1998, 394, 894; Kuziel, W. A. et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 12053; Kurihara, T. et al., J. Exp. Med., 1997, 186, 1757; and Boring, L. et al., J. Clin. Invest., 1997, 100, 2552). Therefore, compounds capable of inhibiting binding of chemokines such as MIP-1 α and/or MCP-1 to the receptors, i.e. chemokine receptor antagonists can be expected to be useful as a drug which inhibits the actions of the chemokines such as MIP-1 α and/or MCP-1 on target cells; however, the drug having the actions is not known.
Cyclic amine derivatives such as various kinds of piperidines or piperazines have recently been reported to have chemokine receptor antagonistic activity (see, for example, WO9724325; Hesselgesser, J. et al., J. Biol. Chem., 1998, 273, 15687; Howard, O. M. Z. et al., J. Med. Chem., 1998, 41, 2184; WO9744329; WO9802151; WO9804554; WO9825605; WO9825617; WO9825604; WO9831364; WO9856771; WO9909984; WO9904794; WO9917773; WO9937617; WO9937619; WO9737651; WO9938514; WO200014086; WO200014089; EP903349; JP9-249566; JP9-25572; and JP11-711350). The compounds, however, are different from the compounds used in the present invention.